A novel approach has been taken to the problem of protein folding that examines more complete ranges of folded topologies. The first stage is to generate all possible shapes for a protein of given size and composition. The second procedure is to generate all conformations, with volume exclusion, upon a lattice in a space restricted to the individual compact space. The advantage of this two stage approach is that there is a high efficiency for conformation generation when there are exactly the same number of points as there are residues. The present studies have aimed at a more thorough evaluation of protein folds, with less than atomic detail. The assumption here is that the overall chain tracing is more important than the precise positioning of each atom. Such atomless structures can be evaluated with potential functions that resemble pairwise residue-residue hydrophobicities. These residue-residue potentials have been extended to include repulsive terms appropriate for packing considerations. Monte Carlo simulations of protein folding with lattice models have shown that folding starts with formation of a nucleus consisting of conservative residues. These residues are much more conservative than other protein residues which are not involved in a nucleus. It suggests that folding nuclei in real proteins may be predicted as the set of most conserved residues. Subjects of other protein studies have included the molten globule, a folding intermediate, use of hydrophobicities to detect binding sites for peptides on protein surfaces, and development of a new matrix to use for sequence comparisons based on the empirical potential energies, and the use of this matrix to understand the stabilities of substitutions in proteins. For studies of HIV protease inhibitor interactions, we have developed new surface area-based interaction potentials. These indicate that almost all inhibitors have similar interactions with the protease; hence escape mutants for any inhibitor will interfere with the interactions of all inhibitors. It is suggested that greater flexibility in the inhibitors might overcome some of the deleterious effects of mutants.